Parkinson's disease is usually characterized as a movement disorder;however cognitive abilities, such as working memory and executive function, decline at early stages of the disease in most patients. The changes in brain that underlie the cognitive deficits are not well understood. We hypothesize that reduced dopamine transmission in the prefrontal cortex in Parkinson's disease is a harbinger of detrimental morphological changes in pyramidal neurons in the prefrontal cortex whose function is necessary for normal cognition. Our data show that a partial loss of dopamine innervation to the prefrontal cortex in monkeys elicited by systemic low-dose MPTP treatment produces cognitive deficits in prefrontal cortex-dependent tasks. Other preliminary data show that there is a decrease of asymmetric (excitatory) synapses on the spines of dendrites on pyramidal neurons in the dorsolateral prefrontal cortex of MPTP-treated monkeys. Together these findings suggest that the number of spine synapses on dendrites in the prefrontal cortex is dopamine-dependent and may be a morphological substrate of the cognitive deficits induced by sustained reductions in dopamine neurotransmission in this region. Modulation of spine synapses number represents a novel neuroplasticity function for dopamine. That cognitive deficits are persistent in the motor-asymptomatic MPTP-treated monkey suggests that this is a good model for the stage of Parkinson's disease in which there are few if any noticeable motor abnormalities, but significant detectable cognitive deficits. The Specific Aims of this proposal will examine this new direction, by investigating the dopamine dependency and specificity of spine synapse changes in the motor-asymptomatic primate MPTP model, examining GDNF gene transfer and pharmacological strategies for their restoration, using biochemical, electron microscopic and behavioral methods, and taking advantage of the primate facilities at the St Kitts Biomedical Research Foundation. This research will use the best animal model available to examine causes and treatments for cognitive decline in Parkinson's disease, which has received scant research attention, despite its substantial impact on patients and caregivers, and ineffectiveness of available therapy. PUBLIC HEALTH RELEVANCE: Parkinson's disease presently affects 1 to 1.5 million Americans, and this number is expected to increase with aging of the population: it is commonly viewed as movement disorder, but it also affects many facets of cognition even at early stages of the disease. The cognitive changes seen in Parkinson's disease are not well understood and have received relatively scant attention in research, despite the substantial impact they have on the patient and caregivers. The proposed research uses a primate animal model to pursue new leads on biochemical and morphological changes in the brain that may underlie the cognitive deficits, and tests novel gene therapy and pharmacological strategies for ameliorating the dysfunction.